History’s largest schizophrenia study has confirmed several predictions about the disorder. One is the notion that calcium signaling pathways—and thus, existing drugs for other disorders, like popular calcium channel blockers—may play a key future role.

Another is the notion that thousands of common gene variants—not a handful of rare ones—are major culprits.

“This study represents a major step forward in our understanding of the genetic basis of schizophrenia,” says Harvard University psychiatry professor Jordan Smoller. Uninvolved in the study, Smoller is Director of the Massachusetts General Hospital Psychiatric and Neurodevelopmental Genetics Unit. “In addition to identifying new loci contributing to the risk for the disorder, the study provides crucial insights into the way forward for unraveling the biological basis of this devastating neuropsychiatric disorder.”

First, says Smoller, the work validates the Genome Wide Association Study (GWAS) approach. Ever-larger patient pools let science “chip away at the so-called 'missing heritability' of schizophrenia and other complex disorders. There has been debate about the value of GWAS for dissecting the genetic basis of disorders like schizophrenia. Studies like this leave no doubt: GWAS works. That's not to say that rare variants are unimportant. But the theory that schizophrenia is simply a heterogeneous collection of many disorders, each caused by rare variants, no longer seems tenable.”

The study, involving researchers from Harvard, Johns Hopkins, and Oxford, among many others, “provides the most informative look at the genetic architecture to date,” Smoller says.  It shows that common SNPs (single nucleotide polymorphisms) “account for most of the genetic variation underlying the risk of schizophrenia, and that each individual risk variant carries a very small effect. That thousands of SNPs contribute.”

Agrees University of Bologna neuro-psychiatrist Alessandro Serretti, also uninvolved in the study: “This study for the first time clearly states what has been previously suggested. There are so many variants that predispose to schizophrenia that it explains why, after more than 20 years of research, no single one has been unequivocally identified. There is a problem of heterogeneity in such large studies. But it paves the way for a future when we will create an individual profile of risk combining the thousands of genetic risk factors for each subject.”

The briefest announcements of the study, published in Nature Genetics and led by the University of North Carolina and the Karolinska Institute, are generating thousands of hits online. In the non-scientific community, the study has re-ignited some “nature vs. nurture” debating. Researchers say both matter, but this study confirms the “nature of the nature” side. That is, the study found that between 50 and 75 percent of the heritability of schizophrenia is due to common genetic variants (arising in more than five percent of the population).

Also important: the discovery that calcium signaling plays a key role, says study lead author Patrick Sullivan. He tells Bioscience Technology: “Our findings strongly point at calcium signaling in nerve cells as playing an important role. Remarkably, two of the genes that stood out in our study make proteins that actually touch each other. These two are critical parts of a "gate" in nerve cells that controls calcium entry. We've never seen this before; that is, GWAS signals in two genes whose protein products are known to have really important functional interactions.”

Will common drugs like calcium channel blockers play a role in schizophrenia treatment? The authors wrote there is “immediate translational relevance.”

Sullivan cautions “a greater understanding of the biology of schizophrenia” is needed. But such understanding may be imminent, since this huge study—of 59,000 subjects—was conducted with “off-the-shelf” technology. “A big step,” he says. “We now have an obvious and affordable path to learning a lot about schizophrenia, one of the diseases in medicine most cloaked in confusion and uncertainty. We estimated the number of places in the genome involved, and provided some signposts for what larger samples will tell us.”

Notes co-author Naomi Wray, a University of Queensland psychiatric geneticist: “This study validates predictions that collecting larger sample sizes would allow identification of more genetic variants associated with schizophrenia. It can be easy to forget, but this was doubted by some when the first GWAS for schizophrenia were published about five years ago. About 3000 cases identified only one associated locus.”

Adds Wray: “This validation is important, providing clear direction for the study of other psychiatric disorders. The effort required in bringing together larger samples with genome-wide genotype data will bear fruit. Identification of genetic risk loci by studying complexity of human genetic variation has been a long time in coming, but is critical for dissecting the complexity of human disease. The identification of 22 genomic loci associated with schizophrenia has pushed a larger wedge in the door to help prise open new insights into the causal mechanisms. The functional follow-up of these loci is still a mountain to climb, but base camp has been located.”

Wrote University Hospital Basel Medical Genetics Director Sven Cichon, at the Schizophrenia Research Forum: “One important message is that increasing the GWAS sample size in a complex neuropsychiatric phenotype such as schizophrenia identifies more common risk loci. In the first-wave schizophrenia mega-analysis two years ago, five risk loci of genomewide significance were detected.” Now, as noted, there are 22.

He added that the genes singled out by Sullivan – CACNA1C and CACNB2 —are relevant to bipolar disorder. “There is growing evidence calcium signaling is involved in both bipolar disorder and schizophrenia. Calcium signaling is a crucial neuronal process and relevant in a number of human diseases, as the authors nicely review. Importantly, calcium channel complexes may be useful for clinical translation, e.g., as drug targets.”

Agrees Smoller: “One of the most exciting messages from this work is that, as larger studies identify a growing catalogue of risk variants, the biological pathways that underlie disease come into focus. This study provides compelling evidence that genes involved in neuronal calcium signaling are important in the etiology of schizophrenia. That's exciting. It supports a growing body of research implicating this biological pathway in a range of psychiatric disorders, including bipolar disorder, depression, and autism. Identifying specific biological pathways, not just individual genes, opens windows we can use to peer into the neurobiology of the disorder. Second, this pathway provides clear possibilities for clinical translation: drugs targeting this pathway, including some already available, may give us novel treatments. That's a really hopeful development. Our current treatments are all based on a small set of targets, and have significant limitations.”